In this study of endothelial injury and endothelial regeneration in large blood vessels (arteries) and small blood vessels (capillaries), we propose to examine: (1) the origin of new endothelial cells; (2) the role of endothelial injury in the development of arterial intimal thickening and atherosclerosis; and (3) factors involved in the neovascularization of healing wounds and tumors. In the section dealing with large vessels, we will exploit a newly devised model in which a localized segment of rat carotid artery is denuded to endothelium (without causing injury to the underlying media) by passing a stream of dry air along the pattern of regrowth (e.g. using scanning electron microscopy) and kinetic studies (e.g. using parabiotic animals). The subsequent development of intimal thickening (detected in pilot studies) will be examined to determine the characteristics and origins of the component cells, the extent of plasma protein penetration into the vessel wall following injury, and the effects of repeated damage, hypertension and a lipid-rich diet. The section dealing with small vessels will concentrate first on establishing the origin of new endothelial cells in growing capillaries in a model of rat granulation tissue, in particular using parabiotic animals to determine the contribution of bone marrow-derived mononuclear cells to neovascularization. Secondly, we propose to develop an in vitro system for the assay of potentially angiogenic or antiotactic agents (e.g. from granulation tissue or tumors), based on an assessment of the outgrowth of capillary sprouts from explants of vascular tissues. The proposed study aims to provide information concerning: (1) mechanisms of atherosclerosis, and (2) vascular factors involved in wound healing and tumor growth. BIBLIOGRAPHIC REFERENCES: Clowes, A.W., Breslow, J.L. and Karnovsky, M.J. Regression of myointimal thickening following carotid endothelial injury and spontaneous development of aortic foam lesions in long term hypercholesterolemic rats. Lab. Invest. 36:73, 1977. Clowes, A.W. and Karnovsky, M.J. Failure of certain antiplatelet drugs to affect platelet deposition and myointimal thickening following arterial endothelial injury in the rat. Lab. Invest., in press, 1977.